Increased myelin in the gray matter of the brain linked to anxiety and PTSD

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Stress resilience and differential symptoms correlate with regional changes in the brain.

A recent study links anxiety behavior in rats to post-traumatic stress disorder (PTSD) in military veterans, an increase in myelin – a substance that speeds up communication between neurons – in areas of the brain associated with emotions and memory.

The results, reported by scientists from University of California, Berkeley, and UC San Francisco (UCSF), provide a possible explanation for why some people are resilient and others vulnerable to traumatic stress, and for the various symptoms – avoidance behavior, anxiety, and fear, for example – triggered by the memory of such stress.

If, as researchers suspect, extreme trauma causes increased myelination, the findings could lead to treatments – drugs or behavioral interventions – that prevent or reverse myelin production and reduce the sequelae of extreme trauma.

Myelin is a layer of fatty substances and proteins that wraps around the axons of neurons – essentially, the insulation around the cabling of the brain – to facilitate long-distance signal transmission and thus communication between areas. away from the brain. The internal regions of the brain appear white – in fact, they are called “white matter” – because of the myelin that envelops the many large bundles of axons there.

FMRI PTSD veteran brain

An fMRI of the brain of a military veteran with PTSD, showing areas of gray matter with increased myelin. Credit: UCSF image by Linda Chao

But the new study reveals increased myelination of axons in so-called “gray matter,” where most of the cell bodies of neurons reside and where most of the cables are less insulated with myelin. The additional myelination was found primarily in areas associated with memory.

Researchers at the San Francisco Veterans Affairs Medical Center performed brain MRI scans of 38 veterans – half with PTSD, half without – and found increased myelination in the gray matter of those with PTSD compared to that seen in the brains of those who do not suffer from PTSD.

Colleagues at UC Berkeley, meanwhile, found a similar increase in myelination in the gray matter of adult rats subjected to an acute stressful event. While not all rats showed long-term effects from stress – just as not all traumatized veterans develop PTSD – those who did had increased myelination in specific areas of the brain associated with severe stress. specific symptoms of stress that were identical to what UCSF doctors found in veterans with PTSD.

Veterans with PTSD and stressed rats who exhibited avoidance behavior, for example, exhibited increased myelination in the hippocampus, often considered the seat of memory. Those who exhibited a fear response had increased myelination in the amygdala, which plays a key role in our response to strong emotions, such as fear or pleasure. Those who suffered from anxiety had increased myelination in the dentate gyrus, an area essential for learning and memory.

“Combining these rat studies with our population of veterans with post-traumatic stress disorder is, for me, really exciting,” said lead author Dr Thomas Neylan, director of the PTSD clinic. Post-Traumatic Stress Disorder (PTSD) Study and Stress and Health Research Program at the San Francisco VA. “At least that’s another mechanism to think about as we develop new treatments. If we see a lasting ability to shape myelin content in an adult brain, perhaps treatments will help reverse this trend. This is where we want to go next with this.

People – and rats – vary in their stress response

The correlation between symptoms and region of myelination was discovered because researchers at UC Berkeley subjected the rats to a battery of more than a dozen tests to assess their specific behavioral response to acute stress.

“We understand that there are a lot of individual variations in humans, but with rats they’re genetically identical, so you think when you put them under stress you’ll get the same response,” the lead author said. Daniela Kaufer, UC Professor of Integrative Biology at Berkeley. “But the answer is extremely variable. They sort of fall into groups, so some are really resilient and some are vulnerable. And those who are vulnerable are vulnerable in different ways: some show avoidance behavior, and some show problems learning out of fear, and some show surprise reactions that are exaggerated. “

Similar individuality is seen in people with PTSD, according to Neylan. The new study suggests that the specific symptoms are linked to newly myelinated areas of the brain.

“There is a lot of heterogeneity between different people with PTSD; it is not a one size fits all. Each patient with PTSD usually has a mix of different symptoms, ”said Neylan, resident professor of psychiatry at the Weill Institute of Neuroscience at UC San Francisco. “Some people are very avoidant. Some people are very hyperreactive. The idea is that if you can show that these different symptom clusters have different neural circuitry, it might actually bring us closer to subtyping people in a way that would allow us to be more focused in our processing.

The researchers, who published their results in December 2021 in the journal Translational Psychiatry, show that stress produces more glial cells in the brain, called oligodendrocytes, which wrap around the axons of neurons and make myelin. The increase in myelin produced by these new oligodendrocytes could affect the speed of connections between neurons, making some connections hypersensitive.

“In the gray matter of your cortex, most dendrites and axons – the projections that come out of neurons that help establish communications with other neurons – can form thousands of connections, and most of them don’t. are not myelinated, ”Neylon said. “But if the experience causes you to start depositing myelin to strengthen certain connections, say your ability to respond quickly to a frightening stimulus, you can speed up that circuit, but you lose the kind of adaptive flexibility that is broader than you.” would normally have mostly unmyelinated axons and dendrites. People with PTSD almost become like a one-note musician – they really know how to react to fear. But this rapid and enhanced response to fear may decrease their adaptive flexibility for non-fear behavior. “

Acute stress boosts oligodendrocytes

In 2014, Kaufer and colleagues at UC Berkeley found that rats under acute stress produced more oligodendrocytes in the gray matter of the brain, especially in the hippocampus. She suggested this led to increased myelination of axons, potentially interfering with the speed at which signals traveled between different areas of gray matter in the brain, such as the hippocampus and amygdala. The new study reinforces this theory.

Neylan was intrigued by the 2014 findings and contacted Kaufer, and they have been collaborating ever since. Neylan partnered with Linda Chao, professor of radiology at UCSF, who developed a way to image myelin in the gray matter of the brain and several years ago scanned the brains of 38 veterans who had suffered severe trauma, some with and others without PTSD.

At the time, scientists looking for changes in myelination linked to brain disorders focused on the white matter in the cortex, which is largely myelinated. In multiple sclerosis, for example, an autoimmune attack destroys the myelin in the white matter. Kaufer may have been the first to find evidence of increased myelination in gray matter associated with the disease.

Chao and Neylan found increased myelination of neurons in the gray matter of veterans with PTSD, but not in those without PTSD. The more severe the symptoms, the greater the myelination.

This led Kaufer and first author Kimberly Long, now a postdoctoral researcher at UCSF, to see if they could also find increased myelin in gray matter after acute trauma in rats. After focusing on the specific symptoms of individual rats with PTSD, they found a correlation between symptoms and myelination in specific regions of gray matter.

Chao then reanalyzed brain scans from his previous group of 38 veterans and found the same correlation: Specific symptoms were associated with myelination in one region of gray matter, but not in others.

Long and Kaufer then used a type of viral gene therapy to increase a transcription factor, called olig1, which increases the production of oligodendrocytes from stem cells in gray matter. When Long injected the virus into the dentate gyrus of rats, the researchers found that it increased the number of oligodendrocytes and generated avoidance symptoms, even without stress.

“The next question was, ‘If I change the genesis of oligodendrocytes, will I change my behavior? Kaufer said. “The start of an answer is here in this article – it’s yes. And now there is a lot more to be done to really understand this.

Neylan, Chao, and Kaufer are collaborating on other studies, including looking for increased myelin in the brains of deceased PTSD patients, improved fMRI imaging of myelin in the brain, to study the effects of chronic stress on brain connections in rats; and to use new high-resolution imaging to study myelin deposition in gray matter.

Reference: “Regional measurements related to oligodendrocytes and gray matter myelin are associated with differential sensitivity to stress-induced behavior in rats and humans” by Kimberly LP Long, Linda L. Chao, Yurika Kazama, Anjile An, Kelsey Y. Hu, Lior Peretz, Dyana CY Muller, Vivian D. Roan, Rhea Misra, Claire E. Toth, Jocelyn M. Breton, William Casazza, Sara Mostafavi, Bertrand R. Huber, Steven H. Woodward, Thomas C . Neylan and Daniela Kaufer, December 13, 2021, Translational Psychiatry.
DOI: 10.1038 / s41398-021-01745-5

The work was supported by a grant from the National Institute of Mental Health of the National Institutes of Health (R01MH115020).

The other co-authors of the article were undergraduates Yurika Kazama, Vivian Roan, Rhea Misra, Anjile An, Kelsey Hu and Claire Toth and doctoral student Jocelyn Breton from UC Berkeley; Lior Peretz, undergraduate from UCLA; Dyana Muller, University of Arizona undergraduate; William Casazza, doctoral student at the University of British Columbia (UBC); professor at UBC Sara Mostafavi; Boston University neurologist Dr. Bertrand Huber; and researcher Steven Woodward of the VA Palo Alto Health Care System.


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